A fundamental problem in neuroscience is mapping physical properties of a stimulus to perceptual characteristics. In vision, wavelength translates into color; in audition frequency translates into pitch. By contrast, the mapping from chemical structure to olfactory percept is unknown. In other words, there is not a scientist or perfumer in the world who can view a novel molecular structure and predict how it will smell. The first step in solving this problem is to link variation in the olfactory receptor to variation in perception. One form of perceptual variation is specific anosmia, which describes an individual with a lowered sensitivity to a specific molecule despite otherwise intact olfactory abilities. This phenotype is thought to reflect polymorphisms in the olfactory receptor genes, much as color-blindness reflects a deficiency in one of the cone receptors in the visual system. Here I propose to study the genetic basis of olfactory perception through the investigation of specific anosmia. This proposal intends to examine how variation in olfactory receptor genes underlies variation in olfactory perception. In Aim 1 I will use a heterologous expression system of human odorant receptors to screen for candidate odorant receptors that respond to isovaleric acid and pentadecalactone-two odorant chemicals implicated in specific anosmia In Aim 2 I will correlate the psychophysical detection threshold clusters of specific anosmia with the underlying receptor's genotype. By focusing on phenotypes that are both easy to psychophysically characterize and involve few genes, we hope to provide the first links between genetic variation and perceptual phenotype in the olfactory system. . Understanding how specific anosmia occurs would allow either specific anosmia or hyposmia to be artificially induced to eliminate or enhance specific odors by producing agonists and antagonists for certain receptor types. In addition, olfaction represents an ideal model system for understanding the genetic basis of multi-factor traits. A number of olfactory genes do not appear to be essential for human fitness, which has allowed a large amount of genetic variation in the genotype. This large natural variation in a model animal (humans) that can clearly describe the perceptual consequences of genotypic variation allows for careful study of the link between genotype and phenotype. [unreadable] [unreadable] [unreadable]